Core A, Abstract This technology core, Metabolomics and Lipidomics Core, aims to provide systems level biochemical insight into the function of key genes, proteins and non-coding RNAs required for adaptation of Mycobacterium tuberculosis (Mtb) to disease relevant stressors. To do so, it will make use of a suite of metabolomic technologies largely pioneered by this core and specifically developed for studies of Mtb physiology. Despite the widely recognized importance of metabolism as a quantitative source of biosynthetic precursors and energy, growing evidence has established its importance as an equally important and specific qualitative mediator of nearly all physiologic processes. Metabolomics is thus emerging as a window into systems level biochemistry. This core will specifically provide biologically unbiased metabo-lipidomic readouts of: (i) the in vitro activities of key genes, proteins and non-coding RNAs required for adaptation of Mycobacterium tuberculosis (Mtb) to disease relevant stressors; and (ii) the identities and activities of their physiologically linked pathways in wild type and genetically engineered Mtb strains. The Core?s Specific Aims are to: (1) Resolve the in vitro biochemical activities of purified recombinant Mtb proteins of unknown function or only class-level annotation; (2) Perform unbiased metabo-lipidomic comparisons of wild type and genetically manipulated Mtb strains; and (3) Perform unbiased activity-based metabolomic comparisons of Mtb proteomes.